The long-term objective of this research theme seeks to identify the most potent components of particulate matter (PM) and to develop strategies for reducing its health impacts. This project focuses on combustion- derived PM (cdPM), and its research is to link molecular pathways in lung cells that are associated with adverse cellular responses to cdPM and adverse human health effects with (a) specific and environmentally relevant cdPM physicochemical properties and (b) changes in these properties as a result of atmospheric transformations and conditioning. The innovation is based on the ability to (a) reliably synthesize cdPM under tightly controlled conditions to obtain specific properties, (b) to mimic key atmospheric transformations, and (c) collect cdPM in a manner that will preserve the properties of interest during exposure of target cells. This approach will minimize confounding factors and enhance the reproducibility of the results, and it will allow the project to explore how these distinct physicochemical properties link to: cellular uptake; toxicity; inflammatory responses; CYP enzyme regulation; and activation of TRP ion channels. Although these are relatively standard measures, these measures are good indicators of in vivo models and human health effects. The Specific Aims include: (1) the completion of a comprehensive career development plan that builds knowledge through hands-on experience and formal training; (2) the synthesis of cdPM generated under conditions that mimic key atmospheric transformations, resulting in real-world differences in shape, size, and composition; and (3) the linking of cdPM physicochemical properties to pathologically important outcomes in primary and immortalized lung cells with in vivo and human-health relevance. Much cdPM exposure is through particle inhalation and interactions with the lung. These research objectives complement the proposal?s comprehensive career development plan that promotes an independent research career for PI, Dr. Kelly. The proposed project focuses on cdPM because it is a significant contributor to atmospheric PM levels, and cdPM emission regulations focus on PM mass concentration. However, changes in cdPM physicochemical properties associated with new fuels and new engine technologies tend to be considered only after these changes have already been implemented, leading to unintended consequences. This application offers an opportunity for a researcher trained in combustion, cdPM generation/characterization to gain skills in biological sciences enabling a more comprehensive and systematic approach to understanding the effects of cdPM physical properties on health and biological outcomes. Completion of the proposed project will provide conclusive new findings about how cdPM size, shape, and composition modify biological processes that may be pivotal in linking air pollution to commonly observed adverse outcomes in respiratory tissue. This information is essential for developing improved metrics that link the PM?s health effects to health outcomes and for developing exposure mitigation strategies tailored to the most potent characteristics of PM.